RESUMEN
There are 500 species of Viola(Violaceae) worldwide, among which 111 species are widely distributed in China and have a long medicinal history and wide varieties. According to the authors' statistics, a total of 410 compounds have been isolated and identified from plants of this genus, including flavonoids, terpenoids, phenylpropanoids, organic acids, nitrogenous compounds, sterols, saccharides and their derivatives, volatile oils and cyclotides. The medicinal materials from these plants boast anti-microbial, anti-viral, anti-oxidant and anti-tumor activities. This study systematically reviewed the chemical constituents and pharmacological activities of Viola plants to provide a basis for further research and clinical application.
Asunto(s)
Viola , Viola/química , Extractos Vegetales/farmacología , Flavonoides , Terpenos/farmacología , ChinaRESUMEN
In this study, novel glycyrrhetinic acid (GA) liposomes modified with a liver-targeting galactosylated derivative ligand (Gal) were prepared using a film-dispersion method. To characterize the samples, particle size, zeta potential, drug loading, and encapsulation efficiency were performed. Moreover, plasma and tissues were pre-treated by liquid-liquid extraction and analyzed by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results showed that the mean residence times (MRTs) and the area under the curve (AUC) of GA liposomes with Gal (Gal-GA-LP), and GA liposomes (GA-LP) were higher than the GA solution (GA-S) in plasma. The tissue (liver) distribution of Gal-GA-LP was significantly different in contrast to GA-LP. The relative intake rate (Re) of Gal-GA-LP and GA-LP in the liver was 4.752 and 2.196, respectively. The peak concentration ratio (Ce) of Gal-GA-LP and GA-LP in the liver was 2.796 and 1.083, respectively. The targeting efficiency (Te) of Gal-GA-LP and GA-LP in the liver was 48.193% and 34.718%, respectively. Taken together, the results indicate that Gal-GA-LP is an ideal complex for liver-targeting, and has great potential application in the clinical treatment of hepatic diseases. Drug loading and releasing experiments also indicated that most liposomes are spherical structures and have good dispersity under physiologic conditions, which could prolong GA release efficiency in vitro.
RESUMEN
Mannose-diester lauric diacid-cholesterol (Man-DLD-Chol), as a liposomal target ligand, was synthesized by lipase catalyzed in a non-aqueous medium. Its chemical structure was confirmed by mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy. Glycyrrhetinic acid (GA) liposomes containing Man-DLD-Chol (Man-DLD-Chol-GA-Lp) were prepared by the film-dispersion method. We evaluated the characterizations of liposomes, drug-release in vitro, the hemolytic test, cellular uptake, pharmacokinetics, and the tissue distributions. The cellular uptake in vitro suggested that the uptake of Man-DLD-Chol-modified liposomes was significantly higher than that of unmodified liposomes in HepG2 cells. Pharmacokinetic parameters indicated that Man-DLD-Chol-GA-Lp was eliminated more rapidly than GA-Lp. In tissue distributions, the targeting efficiency (Te) of Man-DLD-Chol-GA-Lp on liver was 54.67%, relative targeting efficiency (RTe) was 3.39, relative uptake rate (Re) was 4.78, and peak concentration ratio (Ce) was 3.46. All these results supported the hypothesis that Man-DLD-Chol would be an efficient liposomal carrier, and demonstrated that Man-DLD-Chol-GA-Lp has potential as a drug delivery for liver-targeting therapy.
Asunto(s)
Colesterol/química , Ácido Glicirretínico/química , Lipasa/metabolismo , Liposomas/química , Liposomas/metabolismo , Hígado/metabolismo , Manosa/química , Células Hep G2 , Humanos , Lectinas Tipo C , Espectroscopía de Resonancia Magnética , Receptor de Manosa , Lectinas de Unión a Manosa , Receptores de Superficie CelularRESUMEN
Two new clerodane diterpenoids (1-2), one new clerodane diterpenoid alkaloid (3), as well as thirteen known compounds were isolated from Croton crassifolius. The structures of new compounds were established by a combination of spectroscopic methods, including HRMS, (1)H NMR, (13)C NMR, (1)H (1)H COSY, HSQC, HMBC, NOESY and X-ray crystallographic analysis. Compound 3 is firstly reported as the clerodane-type diterpenoid alkaloid in natural products. All of the compounds were evaluated for in vitro cytotoxic activities against CT26.WT cell using the MTT method.
Asunto(s)
Croton/química , Diterpenos de Tipo Clerodano/química , Extractos Vegetales/química , Raíces de Plantas/química , Línea Celular Tumoral , Diterpenos de Tipo Clerodano/aislamiento & purificación , Humanos , Estructura MolecularRESUMEN
In order to quickly and simultaneously obtain the chemical profiles and control the quality of the root of Polygonum multiflorum Thumb. and its processed form, a rapid qualitative and quantitative method, using ultra-high-performance liquid chromatography coupled with electrospray ionization-linear ion trap-Orbitrap hybrid mass spectrometry (UHPLC-LTQ-Orbitrap MS(n)) has been developed. The analysis was performed within 10 min on an AcQuity UPLC™ BEH C18 column with a gradient elution of 0.1% formic acid-acetonitrile at flow rate of 400 µL/min. According to the fragmentation mechanism and high resolution MS(n) data, a diagnostic ion searching strategy was used for rapid and tentative identification of main phenolic components and 23 compounds were simultaneously identified or tentatively characterized. The difference in chemical profiles between P. multiflorum and its processed preparation were observed by comparing the ions abundances of main constituents in the MS spectra and significant changes of eight metabolite biomarkers were detected in the P. multiflorum samples and their preparations. In addition, four of the representative phenols, namely gallic acid, trans-2,3,5,4'-tetra-hydroxystilbene-2-O-ß-d-glucopyranoside, emodin and emodin-8-O-ß-d-glucopyranoside were quantified by the validated UHPLC-MS/MS method. These phenols are considered to be major bioactive constituents in P. multiflorum, and are generally regarded as the index for quality assessment of this herb. The method was successfully used to quantify 10 batches of P. multiflorum and 10 batches of processed P. multiflorum. The results demonstrated that the method is simple, rapid, and suitable for the discrimination and quality control of this traditional Chinese herb.
Asunto(s)
Medicamentos Herbarios Chinos/análisis , Fallopia multiflora/química , Raíces de Plantas/química , Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos/química , Fenoles/análisis , Fenoles/química , Control de Calidad , Espectrometría de Masa por Ionización de Electrospray/métodosRESUMEN
Berberine (BBR), one of the major constituents of Chinese herb Rhizoma coptidis, has been reported to exert beneficial effects to various diseases, including Alzheimer's disease (AD). In the present work, we aimed to investigate the effects of BBR on neuronal cell death induced by homocysteic acid (HCA), which was considered as a risk of AD. BBR significantly reduced HCA-induced reactive oxygen species (ROS) generation, lactate dehydrogenase release and subsequent cell death. LY294002, the PI3K inhibitor, blocked the protection as well as the up-regulation of Akt phosphorylation of BBR. Taken together, our results indicate that BBR protects HCA-induced HT-22 cell death partly via modulating Akt pathway, suggesting BBR may be a promising therapeutic agent for the treatment of HCA-related diseases, including AD.
Asunto(s)
Berberina/uso terapéutico , Homocisteína/análogos & derivados , Proteínas del Tejido Nervioso/fisiología , Neuronas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/fisiología , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Cromonas/farmacología , Evaluación Preclínica de Medicamentos , Homocisteína/toxicidad , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Morfolinas/farmacología , Neuronas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Previous studies have suggested that elevated blood homocysteic acid (HCA) levels increased the risk of Alzheimer's disease (AD), but the underlying mechanisms are unclear. Herein, we studied the neuronal toxicity of HCA and the underlying mechanisms in HT-22 cells. Results showed that HCA induced cell death in concentration- and time-dependent manners, but did not activate Caspase-3. Additionally, HCA increased ROS production, depleted GSH, inactivated the Nrf2/HO-1 pathway, decreased mitochondrial membrane potential and increased the ratio of Bax/Bcl-2, two apoptosis-related proteins. Furthermore, HCA significantly increased the levels of p-JNK and p-c-Jun and its toxicity dramatically attenuated by SP600125, a specific JNK pathway inhibitor. Taken together, our results provide evidence that HCA induced cytotoxicity in HT-22 cells through down-regulating of Nrf2/HO-1 pathway and activating JNK/c-Jun pathway, supporting that HCA might be a therapeutic target for AD.
Asunto(s)
Homocisteína/análogos & derivados , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neuronas/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Estrés Oxidativo/efectos de los fármacos , Animales , Antracenos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Homocisteína/toxicidad , Proteínas de la Membrana/metabolismo , Ratones , Mitocondrias/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Neuronas/enzimología , Neuronas/metabolismo , Síndromes de Neurotoxicidad/enzimología , Síndromes de Neurotoxicidad/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
AIM: Excisanin A, a diterpenoid compound purified from Isodon macrocalyxin D, has anti-cancer properties with little toxicity. In this study, the anti-invasive effects of excisanin A on breast cancer cells and its molecular mechanism of action were investigated. MAIN METHODS: MTT, wound healing, transwell chamber and cell adhesion assays were utilized to investigate the effects of excisanin A on MDA-MB-231 and SKBR3 cells. Western blotting, real-time PCR, RNA interference and luciferase reporter assays were employed to determine the molecular mechanism of action of excisanin A. KEY FINDINGS: Treating MDA-MB-231 and SKBR3 cells with 10-40µM excisanin A significantly inhibited cell migration and invasion and suppressed the mRNA and protein levels of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in a dose-dependent manner. Excisanin A efficiently abolished integrin ß1 expression and reduced the phosphorylation of the downstream kinases focal adhesion kinase (FAK) and Src. Excisanin A inhibited the phosphorylation of phosphoinositide 3-kinase (PI3K), AKT and glycogen synthase kinase 3 beta (GSK3ß) and down-regulated ß-catenin expression and the luciferase activity of the transcription factor LEF-1. Moreover, treating breast cancer cells with siRNA targeting integrin ß1 inhibited cell invasion and migration. SIGNIFICANCE: These results demonstrated that excisanin A inhibited invasion by suppressing MMP-2 and MMP-9 expression; the integrin ß1/FAK/PI3K/AKT/ß-catenin signaling pathway was involved in this process. Therefore, excisanin A might be a potential anti-metastatic chemotherapeutic agent for the treatment of breast cancer.
Asunto(s)
Neoplasias de la Mama/metabolismo , Movimiento Celular/efectos de los fármacos , Diterpenos/farmacología , Quinasa 1 de Adhesión Focal/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas de la Membrana/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , beta Catenina/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/fisiología , Diterpenos/aislamiento & purificación , Diterpenos/uso terapéutico , Femenino , Quinasa 1 de Adhesión Focal/biosíntesis , Humanos , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Proteínas de la Membrana/biosíntesis , Invasividad Neoplásica/patología , Invasividad Neoplásica/prevención & control , Fosfatidilinositol 3-Quinasas/fisiología , Proteínas Proto-Oncogénicas c-akt/biosíntesis , beta Catenina/fisiologíaRESUMEN
Four new ent-kaurane diterpenoids, rabdonervosins G-J (1-4, resp.), were isolated from the leaves and stems of Isodon nervosus. Their structures were elucidated by extensive spectroscopic analyses, including 1D-, 2D-NMR and HR mass spectra. Compound 2 showed potent cytotoxicity against the HepG2 and PC-9/ZD cell lines with IC50 values of 2.36 and 6.07 µM, respectively, and compound 3 exhibited cytotoxicity against the HepG2 and CNE2 cell lines with IC50 values of 8.64 and 9.77 µM, respectively.
Asunto(s)
Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/toxicidad , Componentes Aéreos de las Plantas/química , Extractos Vegetales/química , Extractos Vegetales/toxicidad , Animales , Antineoplásicos/química , Antineoplásicos/toxicidad , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Estructura MolecularRESUMEN
BACKGROUND AND OBJECTIVE: Hirsutanol A is a novel sesquiterpene compound purified from fungus chondrostereum sp in Sarcophyton tortuosum. Its pharmacologic effect has not been reported yet. This study aimed to investigate cytotoxic effect of Hirsutanol A on hepatocellular carcinoma (HCC) cells and its mechanism. METHODS: Hep3B cells were treated with different concentrations of Hirsutanol A. Cell proliferation was detected by MTT assay. The protein expression of LC3 was determined by Western blot. The generation of reactive oxygen species (ROS) was monitored by flow cytometry. RESULTS: Hirsutanol A significantly inhibited proliferation of Hep3B cells with 50% inhibition concentrations (IC50) of 14.54, 6.71, and 3.59 micromol/L when exposed to Hirsutanol A for 24, 48, and 72 h, respectively. Incubation of Hep3B cells with Hirsutanol A markedly increased the level of ROS and the autophagy marker MAP-LC3 conversion from type I to type II. Pre-incubation with an antioxidant N-acetyl cystein (NAC) decreased the level of ROS, and reduced MAP-LC3 I-II conversion, and suppressed cell death. Blocking autophagy with a specific autophagy inhibitor 3-methyladenine (3-MA), the cytotoxic effect of this compound was attenuated. CONCLUSION: Hirsutanol A has potent cytotoxic effect, and can induce autophagic cell death via increasing ROS production.
Asunto(s)
Autofagia/efectos de los fármacos , Carcinoma Hepatocelular , Muerte Celular/efectos de los fármacos , Neoplasias Hepáticas , Especies Reactivas de Oxígeno/metabolismo , Sesquiterpenos/farmacología , Acetilcisteína/farmacología , Adenina/análogos & derivados , Adenina/farmacología , Agaricales/química , Antineoplásicos/administración & dosificación , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Depuradores de Radicales Libres/farmacología , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Proteínas Asociadas a Microtúbulos/metabolismo , Sesquiterpenos/administración & dosificación , Sesquiterpenos/aislamiento & purificaciónRESUMEN
Isodon diterpenoids have received considerable phytochemical and biological attention for their strong antitumor activity with low toxicity. In this study, ExcisaninA, a diterpenoid compound purified from Isodon MacrocalyxinD, was tested on human Hep3B and MDA-MB-453 cell lines and Hep3B xenograft models. The results showed ExcisaninA could inhibit the proliferation of Hep3B and MDA-MB-453 cells via induction of apoptosis, with the evidence of increasing AnnexinV-positive cells and characteristic morphologic changes of apoptosis in the nucleus. Also, ExcisaninA sensitized Hep3B cells to 5-fluorouracil treatment or MDA-MB-453 cells to ADM treatment in vitro. In Hep3B xenograft models, ExcisaninA at 20 mg/kg/d remarkably decreased the xenograft tumor size and induced tumor cells apoptosis using transferase-mediated FITC-12-dUTP nick-end labeling assay. More importantly, we found that ExcisaninA could inhibit AKT activity and block its signal pathway in vitro and in vivo. And treatment with ExcisaninA significantly reduced the number of viable cells in Hep3B/myr-AKT1 cells more than that in control cells. Together, ExcisaninA might be a potent inhibitor of AKT signaling pathway in tumor cells. These data provide validation for the development of ExcisaninA to treat cancers displaying elevated levels of AKT.
Asunto(s)
Neoplasias de la Mama/patología , Carcinoma Hepatocelular/patología , Diterpenos/farmacología , Isodon/química , Neoplasias Hepáticas/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas Dependientes de 3-Fosfoinosítido , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Western Blotting , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Proliferación Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Técnica del Anticuerpo Fluorescente , Humanos , Etiquetado Corte-Fin in Situ , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Three compounds were isolated from Citrus medica L. var. sarcodactylis (Noot) Swingle. The structures were identified as limettin(I), stigmasta-5, 22-dien-3-ol(II) and palmilic acid(III) on the basis of UV, MS, IR, 1HNMR, 13CNMR and DEPT.